Purpose :
Usher syndrome (USH) is characterized by concurrent hearing and vision impairment. There are three clinical types (USH1-3) depending on the severity and age of onset of clinical symptoms. 6-8% of USH1 cases are caused by mutations in the USH1C gene, which encodes the protein harmonin. Mice containing the human USH1C c.216G>A splicing mutation (216A) have a loss of visual function and slow retinal degeneration similar to human Usher syndrome. Antisense oligonucleotides (ASOs) targeting the 216A mutation are known to correct Ush1c splicing and translation, and be efficacious in rescuing hearing and vestibular function when administered systemically. Treatment of ASOs in the eye improves visual function and retinal structures for several months after a single injection. The purpose of this study was to test the effect of multiple ASO treatments on Ush1c expression, visual function and retinal structure in 216AA mice.

Methods :
Various of doses of 216A-targeted ASOs were delivered locally to the eye by intravitreal injection (IVI) in 216AA mutant and control-treated littermate mice. The expression of Ush1c splice variants in the retina was determined by reverse transcription-polymerase chain reaction (RT-PCR). Visual function and retinal structures were evaluated by electroretinogram (ERG) and optical coherence tomography (OCT) imaging analyses, respectively.

Results :
RT-PCR analysis of retinal RNA isolated from 216AA mice treated with various doses of ASOs demonstrated a dose-responsive correction in Ush1c splicing. ERG and OCT analysis showed significant improvements in photoreceptor function and structure, respectively, after a single IVI treatment of ASO in neonatal and adult 216AA mutant mice compared to control mice. These effects were sustained for 3 months. Additional ASO treatments increased the duration of efficacy for visual function.

Conclusions :
Our results show that ASOs delivered locally to the eye can effectively target Ush1c mutations in the retina. These results suggest the therapeutic potential of early ASO intervention to improve gene expression, photoreceptor structure and function in Usher syndrome.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.